Novel halo-substituted active methylene compounds

ABSTRACT

A novel process for the preparation of compounds of formula I  
                 
 
by employing novel halo-substituted active methylene compounds of formula III and process of preparation thereof.

TECHNICAL FIELD

The present invention relates to a novel halo-substituted activemethylene compounds and a process for preparation of the same. Moreparticularly, the present invention relates to a process for preparationof compounds of formula I by employing novel halo-substituted activemethylene compounds of formula III.

BACKGROUND

U.S. Pat. No. 5,124,482 and U.S. Pat. No. 5,216,174 discloses themanufacture and use of4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutane amidefor preparation of[R-(R*,R*)]-2-(4-Fluorophenyl)-B,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1h-Pyrrole-1-Heptanoic Acid.[R-(R*,R*)]-2-(4-Fluorophenyl)-B,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)Carbonyl]-1h-Pyrrole-1-HeptanoicAcid is inhibitor of HMG CoA reductase and thus is used asantihypercholesterolemic agent. Hitherto unknown compounds of theformula III

are extremely useful novel intermediates for an improved process for thepreparation of4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzenebutaneamide(Scheme 1).

SUMMARY OF THE INVENTION

The present invention also relates to a process for preparation of novelintermediates of formula III.

The present invention also relates to novel process for preparationcompounds of formula I.

As mentioned earlier the compounds of formula I can be prepared by anovel process comprising,

-   -   a) a) halogenation of compound of formula II to afford a        compounds of formula III,    -   b) reaction of compounds of formula III with compounds of        formula IV.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula I are important intermediates for the preparationof drug molecules especially, HMG Co-A reductase inhibitors. The HMGCo-A reductase inhibitors are useful as inhibitors of the enzyme3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) andare thus useful as hypolipidemic or hypocholesterolemic agents.

FORMULA I

The process of the present invention is new, economical, andcommercially feasible method for preparing intermediates used for thepreparation of HMG CoA reductase inhibitors.

The reaction between compounds of formula II and III is carried out inthe presence of reagents selected from Bromine, N-bromosuccinimide,thionyl chloride, Br₂(CN)₂, 4-(dimethylamino)pyridinium bromide or anysuch suitable halogenating agent.

The compounds of formula III can be further used for preparation of4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzene butane amidewhich is key intermediate for manufacture of[R-(R*,R*)]-2-(4-Fluorophenyl)-B,D-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino) Carbonyl]-1h-Pyrrole-1-Heptanoic Acid, by reacting with compoundof formula IV.

The reaction between compounds of formula III and formula IV is carriedout in the presence of reagents selected from Lithium diisopropylamide,sodium hydride n-butyllithium, sodium ethoxide or any such suitablebase.

The following non-limiting examples illustrate the inventors' preferredmethod for preparing the compounds of the invention.

EXAMPLES Example 1 Preparation of 2-Bromo-4-methyl-3-oxo-pentanoic AcidPhenylamide

To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048mol) in chloroform (100 mL), liquid bromine (7.8 g, 0.048 mol) wasadded. After stirring for 30 minutes, the reaction mixture wasconcentrated and product was isolated by column chromatography (silicagel: 60-120 mesh, eluent: Pet. Ether/ethyl acetate-60:40).

Yield: 11.0 g, 80%

Example 2 Preparation of 2-Bromo-4-methyl-3-oxo-pentanoic AcidPhenylamide

To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048mol) in acetone 100 mL), N-bromosuccinimide (8.5 g, 0.048 mol) wasadded. After stirring for 3 hours, the reaction mixture was concentratedand product was isolated by crystallization from Pet. Ether/ethylacetate.

Yield: 12.5 g, 92%

Example 3 Preparation of4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzene Butane Amide

To a chilled solution of diisopropylamine (8 mL, 0.056 mol) in dryTHF(50 mL), n-butyl lithium (35 mL, 1.6 M, 0.056 mol) in hexane wasadded dropwise under nitrogen atmosphere, maintaining the temperaturebetween −10° C. and −25° C. and stirred for 30 minutes at the sametemperature. A solution of 1-(4-Fluoro-phenyl)-2-phenyl-ethanone (10 g,0.047 mol) in THF (20 mL) was added to the reaction mixture dropwise,maintaining the temperature between −60° C. and −78° C. and stirred for1 hour at the same temperature. 2-Bromo-4-methyl-3-oxo-pentanoic acidphenylamide (13.4 g, 0.047 mol) in THF (30 mL) was added dropwise to thereaction mixture, maintaining the temperature between −60° C. and −78°C. and stirred for 30 minutes. The reaction mixture was slowly warmed10-15° C., over a period of 1 hour and quenched with water (50 mL). Theproduct was extracted with ethyl acetate (2×50 mL). Combined organicextract was washed with water (2×50 mL) brine (2×50 mL) and concentratedto obtain title compound.

Yield: 16 g, 85%.

Example 4 Preparation of4-Fluoro-α-[2-methyl-1-oxopropyl]γ-oxo-N-β-diphenylbenzene Butane Amide

To a chilled solution of diisopropylamine (8 mL, 0.056 mol) in dry THF(50 mL), n-butyl lithium (35 mL, 1.6 M, 0.056 mol) in hexane was addeddropwise under nitrogen atmosphere, maintaining the temperature between−10° C. and −25° C. and stirred for 30 minutes at the same temperature.A solution of 1-(4-Fluoro-phenyl)-3-methyl-butan-1-one (8.4 g, 0.047mol) in THF (20 mL) was added to the reaction mixture dropwise,maintaining the temperature between −60° C. and −78° C. and stirred for1 hour at the same temperature. 2-Bromo-4-methyl-3-oxo-pentanoic acidphenylamide (13.4 g, 0.047 mol) in THF (30 mL) was added dropwise to thereaction mixture, maintaining the temperature between −60° C. and −78°C. and stirred for 30 minutes. The reaction mixture was slowly warmed10-15° C., over a period of 1 hour and quenched with water (50 mL). Theproduct was extracted with ethyl acetate (2×50 mL). Combined organicextract was washed with water (2×50 mL) brine (2×50 mL) and concentratedto obtain title compound.

Yield: 15 g, 87%.

1. A process for preparing compound of formula I

comprising the steps of reaction of the compound of formula III withcompounds of formula IV to obtain compound of formula I


2. A process as in claim 1, wherein the reaction between compounds offormula III and formula IV is carried out in the presence of reagentsselected from lithium diisopropylamide, sodium hydride n-butyllithium,sodium ethoxide or any such suitable base.
 3. A process as in claim 1,wherein the compounds of formula III is prepared

by halogenation of compound of formula II to afford a compound offormula II.


4. A process as in claim 3, wherein the halogenation is carried out inthe presence of reagents selected from Bromine, N-bromosuccinimide,thionyl chloride, Br₂(CN)₂, 4-(dimethylamino)pyridinium bromide or anysuch suitable halogenating agent.
 5. An intermediate of formula III